Natural products represent an excellent source of novel chemical scaffolds that are inherently biologically active. It has been estimated that 78% of the 90 antibacterial agents and 62% of the 79 anticancer agents approved for use in the US over the past two decades have their origins in natural products. With advances in robotics, High Throughput Screening (HTS) has become the primary approach used worldwide to discover new lead compounds for drug development and chemical probes to better understand the disease process. Unfortunately, natural products extracts are not readily amenable for use in discovery programs that use HTS which has led to a significant reduction in opportunities for new drug and chemical probe discovery. The current proposal seeks to overcome this obstacle by creating a unique library of marine natural products (both enriched fractions and purified compounds) that is compatible with HTS and is available to the Life Sciences Research Community as a new research tool. In this two year project we seek to create a unique library of marine natural products, designated as the Harbor Branch Oceanographic Institute (HBOI) Marine Natural Product Library (MNPL), which will serve as a long term resource to the scientific community. HBOI has been engaged in the production of such a library for the past five years as part of a National Cooperative Drug Discovery Project and has successfully created a library from approximately 150 organisms. Screening of the existing chemical library has allowed for the rapid discovery of many new structures including novel histone deacetylase inhibitors, MCL-1 inhibitors, anti-malarial agents and inhibitors of nuclear factor kappa B. HBOI has a repository of over 14,000 frozen marine specimens and 19,000 marine microbial isolates that could be used in generation of an expanded Marine Natural Products Library. In the current proposal we seek to greatly expand the diversity of the library through adding automation to the fractionation process and hiring new graduates and students to conduct chemical fractionation on 750-1250 organisms found in the HBOI Frozen Organism Repository and 250-350 organisms from the Marine Microbial Culture Collection. The library will be made available to external collaborators through material transfer agreements, collaborative research agreements and sponsored research projects. Public Health Relevance: This project will create a unique resource - the HBOI Marine Natural Products Library- for the discovery of biological probes and new medicines. This resource will be a library of pure and enriched fractions derived from marine organisms that will be available for screening by the High Through put Screening Community. Such a library will provide access to unique chemical diversity to enhance the US Life Science Research Enterprise.